Case ReportAn Unprecedented Case of p190 BCR-ABL Chronic MyeloidLeukemia Diagnosed during Treatment for Multiple Myeloma: ACase Report and Review of the Literature

Kosuke Miki,1 Naoshi Obara ,2 Kenichi Makishima,2 Tatsuhiro Sakamoto,2

Manabu Kusakabe,2 Takayasu Kato,2 Naoki Kurita ,2 Hidekazu Nishikii,2

Yasuhisa Yokoyama ,2 Mamiko Sakata-Yanagimoto,2 Yuichi Hasegawa ,2

and Shigeru Chiba2

1School of Medicine, University of Tsukuba, Tsukuba, Japan2Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan

Correspondence should be addressed to Naoshi Obara; n-obara@md.tsukuba.ac.jp

Received 19 August 2018; Accepted 26 September 2018; Published 10 October 2018

Academic Editor: Massimo Breccia

Copyright © 2018 Kosuke Miki et al. ,is is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

We report the case of a 76-year-old man who was diagnosed as having chronic myeloid leukemia (CML) with p190 BCR-ABLwhile receiving treatment for symptomatic multiple myeloma (MM). ,e diagnosis of MM was based on the presence of serumM-protein, abnormal plasma cells in the bone marrow, and lytic bone lesions. ,e patient achieved a partial response tolenalidomide and dexamethasone treatment. However, 2 years after the diagnosis of MM, the patient developed leukocytosis withgranulocytosis, anemia, and thrombocytopenia. Bone marrow examination revealed Philadelphia chromosomes and chimericp190 BCR-ABL mRNA. Fluorescence in situ hybridization also revealed BCR-ABL-positive neutrophils in the peripheral blood,which suggested the emergence of CMLwith p190 BCR-ABL. ,e codevelopment of MM and CML is very rare, and this is the firstreport describing p190 BCR-ABL-type CML coexisting with MM. Moreover, we have reviewed the literature regarding thecoexistence of these diseases.

1. Introduction

Multiple myeloma (MM) is a lymphoid cancer that ischaracterized by monoclonal proliferation of malignantplasma cells in the bone marrow, monoclonal protein in theserum, and organ dysfunction [1]. Chronic myeloid leu-kemia (CML) is a clonal disorder of myeloid origin that ischaracterized by the Philadelphia chromosome, t(9; 22)(q34; q11), in which the BCR-ABL fusion gene is created.Several types of BCR-ABL are known, with the p210 andp190 types being the most common, distinguished by thebreak point in the BCR gene.,e vast majority of CML casesresult from the p210-type of BCR-ABL, while the p190-typeis rarely found in CML [2].,e coexistence of MM and CMLin the same patient is rare, with only 22 reported cases[3–23], all involving p210 BCR-ABL. ,erefore, we report

a case of coexisting MM and CML with p190 BCR-ABL.Given the rarity of this case, we also discuss the origins ofthese hematologic malignancies and review the relevantliterature.

2. Case Report

A 76-year-old man was referred to our hospital in September201X, because of right leg pain, lower back pain,and weight loss of 3 kg. Lumbar magnetic resonance im-aging and computed tomography (CT) suggested thepresence of lumbar spinal canal stenosis and a sacral tumor(Figure 1(a)). Laboratory testing revealed a markedly el-evated serum IgG level (5,436mg/dL, normal: 800–1,800mg/dL) and an elevated serum beta-2 microglobulinlevel (4.1 µg/mL, normal: 0–3 µg/mL), although there were

HindawiCase Reports in HematologyVolume 2018, Article ID 7863943, 5 pageshttps://doi.org/10.1155/2018/7863943

no signs of anemia, renal dysfunction, or proteinuria.Serum immunofixation revealed IgGκ-type M-protein,with an estimated serum-free κ and λ chain ratio of 21.5 : 1(Figure 1(b)). Microscopic examination and flow cytometricanalysis of bone marrow aspirate revealed elevated numbersof CD138-positive abnormal plasma cells. Cytogeneticanalysis of the bone marrow revealed 46XY, and the patientwas diagnosed as havingMM (R-ISS, stage II). Chimeric p190BCR-ABL mRNA was not detected in the bone marrowsample at this point. ,e patient underwent two cycles ofbortezomib plus dexamethasone and two cycles of

cyclophosphamide, bortezomib, and dexamethasone (CBD)but did not respond to either treatment regimen. ,etreatment was switched to lenalidomide (25mg/day) plusdexamethasone (20mg/week; Ld therapy), and there wasa marked response, with a substantial decrease in theM-protein and disappearance of the sacral tumor on CT.After 24 cycles of Ld therapy, the patient achieved a partialresponse based on the International Myeloma WorkingGroup criteria.

In December 201X+2, the patient developed leukocytosis(white blood cell count: 35.8 × 109/L) and thrombocytopenia

(a) (b)

Figure 1: (a) Computed tomography (CT) at the time of multiple myeloma (MM) diagnosis. Sacral tumor and lytic bone involvement in thelumbar spine are shown (arrow). (b) Serum immunofixation at the time of MM diagnosis. SP, size marker; G IgG; A IgA; M IgM; κ, kappachain; λ, lambda chain.

1 2 3 4 5 76

1 2 3 4 5

6 7 8 9 10 11 12

13 14 15 16 17 18

19 20 21 22 X Y

(b)

(c)(a)

Figure 2: (a) Karyotype from a bone marrow specimen at the time of chronic myeloid leukemia (CML) diagnosis. t(9; 22) is shown by usingarrows. (b) Fluorescence in situ hybridization for peripheral blood cells. Arrowheads, BCR-ABL fusion gene (yellow); large arrows, ABLsignal (red); small arrows, BCR signal (green). (c) Polymerase chain reaction (PCR) amplification analysis from the bone marrow specimentaken at the time of CML diagnosis. Lane 1, size marker; lane 2, p210 negative control; lane 3, p190 negative control; lane 4, p210 positivecontrol; lane 5, p190 positive control; lane 6, p210 patient’s sample; lane 7, p190 patient’s sample.

2 Case Reports in Hematology

Table 1: Concomitant multiple myeloma and chronic myeloid leukemia cases.

Pt Age/Sex Year Firstdisease

Diagnosisinterval(month)

Type ofM-protein

,erapy forMM

,erapy forCML

Confirmationmethod of Ph+

Typeof Ph Reference

1 77M 1972 MM 33 BJP No treatment Notreatment Chr MacSween and

Langley [3]

2 65/F 1974 CML 113 IgG-κ No treatment Busulfan Chr Derghazarian andWhittemore [4]

3 58/M 1982MMandCML

Simultaneous IgG-κ MP, RT HU,Busulfan, Chr Boots and Pegrum

[5]

4 71/M 1993 MM 24 IgG-κ MP, RT HU Chr Klenn et al. [6]

5 72/F 1998MMandCML

Simultaneous IgG-κ VP IFN-α Chr, PCR, FISH P210 Tanaka et al. [7]

6 70/M 1999 MM 33 IgG-κ Not reported Notreported Chr Nitta et al. [8]

7 81/M 2001MMandCML

Simultaneous IgA-κ MP Notreatment Chr, PCR Alvarez-Larran

et al. [9]

8 66/M 2003MMandCML

Simultaneous IgG-κ MP INF-α, HU,Busulfan Chr, PCR, FISH P210 Schwarzmeier et al.

[10]

9 47/M 2003 MM 33 BJP LOAD-IN Notreported Chr Nakagawa [11]

10 68/M 2005 CML 20 IgG-λ MP IFN-α,imatinib Chr, PCR P210 Garipidou et al. [12]

11 85/F 2005MMandCML

Simultaneous IgG-λ Not reported Notreported Chr, PCR P210 Wakayama et al.

[13]

12 76/M 2009 CML 14 IgA-κ MP IFN-α,imatinib Chr, PCR, FISH P210 Galanopoulos et al.

[14]13 57/F 2009 CML 65 IgA-κ TD, VAD Imatinib Chr, PCR P210 Michael et al. [15]14 72/F 2010 CML 3 IgG-κ No treatment Imatinib Chr, PCR P210 Ide et al. [16]

15 71/F 2012MMandCML

Simultaneous IgG-κ MP, Bd, Ld Imatinib Chr Offiah et al. [17]

16 64/F 2013MMandCML

Simultaneous IgA-κ BD Imatinib Chr Romanenko et al.[18]

17 62/F 2013 MM 17 IgG-κ RT, VCD,VCDD, VRD Dasatinib Chr, PCR P210 Ragupathi et al. [19]

18 77/M 2014MMandCML

Simultaneous IgG-κ RT, BD Notreatment Chr, PCR P210 Maerki et al. [20]

19 60/M 2014 MM 48 IgG-κ RT, Ld HU,dasatinib Chr, FISH Alsidawi et al. [21]

20 63/F 2012 CML 120 IgG-κ BD, Ld Imatinib Chr, PCR P210 Pessach et al. [22]21 68/M 2012 MM 54 IgG-λ VAD Imatinib Chr, PCR P210 Pessach et al. [22]22 76/M 2015 CML 38 IgA-λ No treatment Imatinib Chr, PCR Ahn et al. [23]

23 51/F 2016 MM Unknown IgG BD Imatinib Chr, PCR Wolleschak andHeidel [24]

24 88/M 2016MMandCML

Simultaneous IgD-κ VRD Imatinib Chr Ali et al. [25]

25 76/M 2018 MM 28 IgG-κ Ld Dasatinib,bosutinib Chr, PCR, FISH P190 Our case

BJP, Bence Jones protein; MP, melphalan, prednisolone; RT, radiation therapy; HU, hydroxyurea; LOAD-IN, melphalan, ranimustine, vincristine, IFN-α;PSL, prednisolone; VCD, bortezomib, cyclophosphamide, dexamethasone; VCDD, VCD plus doxorubicin; VRD, bortezomib, lenalidomide, dexamethasone;Ld, lenalidomide, dexamethasone; VAD, vincristine, doxorubicin, dexamethasone; BD, bortezomib, dexamethasone; CBD, BD plus cyclophosphamide; Rd,lenalidomide, dexamethasone; TD, thalidomide, dexamethasone; Chr, chromosome; PCR, polymerase chain reaction; FISH, fluorescence in situhybridization.

Case Reports in Hematology 3

(platelet count: 3 × 109/L). Bone marrow biopsy and aspi-ration revealed hypercellularity with a marked increase inmyeloid lineage cells but without an increase in blast cells(4%). Cytogenetic analysis revealed 46XY t(9; 22) (q34;q11.2) in 20 of 20 cells, and fluorescence in situ hybridization(FISH) analysis revealed that 99.5% of the cells were positivefor BCR-ABL. Peripheral blood neutrophils were also pos-itive for BCR-ABL (98.8%) (Figures 2(a)–2(b)). Chimericp190, but not p210, BCR-ABL mRNA was detected by usingpolymerase chain reaction (Figure 2(c)). ,e diagnosis wasconfirmed to be CML with p190 BCR-ABL in the acceleratedphase (AP), which coexisted with MM (a maintained partialresponse). Dasatinib treatment (100mg/day) was startedimmediately. ,e dose was subsequently decreased to50mg/day, due to the persistence of thrombocytopenia. InApril 201X+3, a bone marrow examination indicated thatthe patient had achieved a second chronic phase, with 31% ofthis cells being positive for BCR-ABL upon FISH analysis,and that his peripheral blood count had normalized.However, 5 months later, FISH analysis revealed that 85.8%of his bone marrow cells were positive for BCR-ABL, andsubsequently, his treatment was changed from dasatinib tobosutinib. ,is switch appeared to be ineffective, as nodecrease in the BCR-ABL-positive bone marrow cells wasdetected after 2 months.

3. Discussion

,ere have only been 24 cases of coexisting MM and CMLreported (Table 1) [3–25]. MM and CML were diagnosedsimultaneously in 9 cases, and the diagnoses were sequentialin the remaining cases, with MM being diagnosed first in 8cases and CML being diagnosed first in 7 cases. Among theprevious reports, all genotypes confirmed by PCR werep210-CML in patients with coexisting MM and CML. Ourcase is the first reported ofMM coexisting with p190-CML inthe same patient. ,e intervals between the sequential di-agnoses ranged from 3 months to 120 months. Multiplepossibilities could be considered regarding the associationbetween MM and CML. First, these two malignancies couldoccur independently, and their coexistence, while very rare,could be simply coincidence. Second, common precursors,referred to as “clonal hematopoiesis of indeterminate po-tential (CHIP),” give rise to both MM and CML cells ina patient. Given our patient’s relatively advanced age, it ispossible that CHIP had a common origin, although we haveno direct evidence to support this possibility. A third pos-sible explanation is that the second disease might bea therapy-related malignancy that develops after treatmentfor the first disease. In the present case, the diagnosis of MMwas followed by that of CML. ,e frequency of secondarycarcinogenesis in patients with MM was evaluated for co-horts participating in clinical trials with lenalidomide, whichwere conducted from 2000 through 2012 [24]. ,is reportshowed that the incidence of secondary hematologic ma-lignancies was increased in patients who concurrently re-ceived melphalan and lenalidomide, while it did not increasein those receiving other treatment protocols, regardless ofwhether lenalidomide was included [26]. ,ere is no clear

evidence that lenalidomide is carcinogenic, and there hasonly been one reported case of CML that developed afterlenalidomide treatment. ,erefore, the increased incidenceof hematologic malignancies has been attributed to mel-phalan, because alkylating agents such as melphalan areknown to cause therapy-related myelodysplastic syndromes.According to previous case reports of MM coexisting withCML, many patients received alkylating agents as treatmentfor MM (Table 1). In the present case, a small dose of analkylating agent (cyclophosphamide; total: 2,400mg/m2)was administered during two cycles of CBD therapy. We,therefore, needed to consider the possibility that the cy-clophosphamide treatment caused the CML. However, anaccumulation of case reports and further investigations arerequired to draw definitive conclusions.

Although p190 BCR-ABL CML has been reported in 1%of CML cases, there have been several clinical observationssuggesting that CML with p190 BCR-ABL is difficult to treat[27]. Furthermore, p190 BCR-ABL has been identified asa marker for high-risk disease, and early stem cell trans-plantation has been recommended if the patient is eligible[26]. Our patient received initial treatment of dasatinib forhis CML in AP with p190 BCR-ABL, which provideda partial cytogenetic response at 4 months after the di-agnosis. Although the long-term effects of dasatinib treat-ment in patients with p190 BCR-ABL CML are unknown, inthe present case, the duration of response to dasatinib wasrelatively short.

Ethical Approval

,is study was adhered to the tenets of the Declaration ofHelsinki.

Consent

Informed consent was obtained from the patient.

Conflicts of Interest

,e authors declare that they have no conflicts of interest.

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4 Case Reports in Hematology

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